New antiplatelet drugs: beyond aspirin and clopidogrel

Antiplatelet therapy remains a cornerstone of modern management of atherothrombotic vascular disease. For many years, aspirin has been the mainstay of initial antiplatelet drug management in coronary heart disease, while the need for inhibition of other platelet activation pathways has led to the development of various other antiplatelet drugs, such as clopidogrel. An improved understanding of the underlying mechanisms involved in thrombogenesis has paved the way for further development of newer antiplatelet drug therapies. Various clinical studies have probed the effectiveness and risk profile of the newer antiplatelet drugs, such as prasugrel, in comparison with currently available drugs. Some newer agents such as prasugrel are close to being approved for clinical use, whereas other agents such as cangrelor and AZD6140 are in phase 3 clinical trials. New drug classes, such as the thromboxane receptor antagonists (such as NCX‐4016 and S18886), as well as platelet adhesion antagonists and thrombin receptor antagonists are similarly being evaluated for their efficacy and risk profile in phase I and II trials.     

新药时代自体造血干细胞移植在多发性骨髓瘤一线治疗中的地位

多发性骨髓瘤(multiple myeloma, MM)患者的总生存期(overall survival, OS)在过去20年间从3年延长至8~10年, 这得益于蛋白酶体抑制剂和免疫调节药物等的广泛应用。即使在新药时代, 自体造血干细胞移植(autologous stem cell transplantation, ASCT)仍可显著提高移植后反应率, 增加微小残留病变阴性率, 延长无进展生存期。ASCT对OS的影响在不同研究中结果并不一致, 这主要与进展后采用不同治疗方案有关。随着更多新药的出现, ASCT后复发患者会有更多选择。故新药时代, ASCT仍是MM患者诱导治疗后的一线巩固方案。     

Sickle cell disease in the new era: advances in drug treatment

Sickle cell disease is an inherited blood disorder afflicting an estimated 100,000 individuals in the United States and over 20 million people worldwide. The disease is heralded as the first molecular disease. However, despite its genetic simplicity, the pathophysiologic processes leading to its clinical sequelae are complex, heterogeneous and interrelated, making drug development to treat the disease challenging. For over two decades only one drug, hydroxyurea, had been used as disease-modifying therapy. New pharmacologic agents are rapidly evolving with three new drugs, with different mechanisms of action, approved by the United States Food and Drug Administration in recent years (L-glutamine, crizanlizumab and voxelotor). Several therapeutic approaches targeting different pathways in the disease pathophysiology are being investigated. These include inhibition of hemoglobin S polymerization such as by fetal hemoglobin induction or by increasing hemoglobin oxygen affinity, as well as intervention of downstream pathways including inhibiting cellular adhesion, reducing inflammation and oxidant stress, modulating platelet activation and coagulation abnormalities, and targeting nitric oxide signaling. This review will provide an overview of these therapeutic strategies, discuss the four currently approved drugs in detail, and summarize ongoing clinical trials of new drugs or drug indications for the treatment of sickle cell disease in different phases of development excluding those related to cellular therapies.     

Clopidogrel's role in the management of atherosclerotic disease: a focus on acute coronary syndromes

Recent advances in our understanding of the role of the platelet in the atherosclerotic process beyond the acute formation of arterial blood clots, such as inflammation, have highlighted the role of antiplatelet agents as being much more than just 'blood thinners.' Some of the most important cardiovascular trials performed in the last 20 years have studied antiplatelet therapies. However, despite their long history, current global health implications and proven benefit, there remain substantial gaps in our understanding as to how to best utilize the limited number of antiplatelet agents available. This article will discuss the mechanism of action of the antiplatelet class known as thienopyridines, the pharmacodynamics and pharmacokinetics of the thienopyridine agent clopidogrel (Plavix, Bristol-Myers Squibb and Sanofi Pharmaceuticals) as well as the literature supporting its clinical benefits and areas of ongoing research that will help clarify the optimal utilization of clopidogrel for the treatment of cardiovascular disease.     

Therapeutic vaccines in metastatic castration-resistant prostate cancer: principles in clinical trial design

Although docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer in 2004, additional therapies are still required. Prostate cancer is often slow-growing and expresses many tumor-associated antigens, making it a feasible target for immunotherapy. Several therapeutic cancer vaccines have been developed for prostate cancer, including antigen-presenting-cell-based, vector-based, and whole tumor cell vaccines. Initial trials demonstrated that vaccine approaches have limited toxicity. Clinical trials of targeted biologic therapies have demonstrated that patient selection is vital, and there is preliminary evidence that clinical parameters can be used to encompass metastatic prostate cancer patients who will more probably respond to vaccine treatment. In addition to appropriate patient selection, a successful clinical trial must have an appropriate primary endpoint as well. Three randomized, ‘placebo’-controlled studies in metastatic castration-resistant prostate cancer have suggested a clinically significant survival advantage in spite of a lack of improvement in time to progression, implying that overall survival is the ideal endpoint for such trials. Careful examination of data from completed immunotherapy clinical trials in prostate cancer has identified appropriate patient populations and endpoints. Those principles need to be applied to future trial design to properly evaluate prostate cancer vaccines.     

Pregnancy and medications for inflammatory bowel disease: An updated narrative review

Inflammatory bowel disease (IBD) is often diagnosed during the peak reproductive years of young women. Women with active IBD around conception are at a significantly increased risk of disease relapse during pregnancy, which is associated with poor pregnancy and neonatal outcomes. Given these substantial risks, it is prudent that disease remission should ideally be achieved before conception. Unfortunately, some patients may experience a disease flare-up even if they are in a state of remission before pregnancy. Patients must continue their IBD medications to reduce the risk of disease flare and subsequent poor outcomes during the gestational and postpartum periods. When treating IBD flare-ups during pregnancy, the management is quite similar to the therapeutic approach for non-pregnant patients with IBD, including 5-aminosalicylate, steroids, calcineurin inhibitors (CNIs), and biologic therapies. While the data regarding the safety of CNIs in pregnant women with IBD is limited, the findings in our recent meta-analysis suggest that CNIs may be safer to use in those with IBD than in solid organ transplant recipients. There are several types of biologics and small-molecule therapies currently approved for IBD, and physicians should thoroughly understand their clinical benefits and safety profiles when utilizing these treatments in the context of pregnancy. This review highlights recent studies, including our systematic review and meta-analysis, and discusses the clinical advantages and safety considerations of biologics and small molecules for pregnant women with IBD.     

Immunotherapy in hepatocellular carcinoma: Combination strategies

Liver cancer is one of the most common causes of cancer death globally, and its incidence in the United States is increasing. Patients with advanced hepatocellular carcinoma (HCC) who are not candidates for surgical resection, liver transplant, or locoregional therapies can be treated with systemic therapies. Multiple agents, including sorafenib, lenvatinib, and regorafenib are approved for use as either first- or second-line therapy in this patient population, but all have relatively modest survival benefits. HCC is potentially susceptible to therapy with checkpoint inhibitors, including agents such as nivolumab and pembrolizumab, which are both approved by the Food and Drug Administration for patients previously treated with sorafenib but have not demonstrated superior overall survival in phase III trials. It is clear that more effective approaches are needed to potentiate the effects of checkpoint inhibitors in patients with HCC. This review will outline and appraise the current literature on the use of checkpoint inhibitors in HCC as part of a combination treatment involving an additional mode of therapy. The list of agents that can be paired with checkpoint inhibitors includes an additional checkpoint inhibitor, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors, tyrosine kinase inhibitors, OX-40 agonists, and PT-112 inhibitors. The main non-pharmacologic therapies currently being studied for inclusion in a combination strategy include radiation therapy, trans-arterial chemoembolization, and ablation.     

Targeted therapies of metastatic breast cancer: Relationships with cancer stem cells

In the last years, many targeted agents have been developed for metastatic breast cancer (MBC) treatment and are being tested in clinical trials. In spite of this, apart from epidermal growth factor receptor 2 (HER2) positive subset, no significant increase in the median overall survival (OS) has been reported. Similarly to conventional chemo- and radiotherapy, the cancer stem cell theory has been evoked to explain the frustrating results often obtained with this emerging category of drugs. This review examines the results in MBC of the approved targeted therapies or those currently under evaluation in experimental studies or in clinical trials, in the light of their relationships with breast CSCs and of the efforts to circumvent the development of resistance. In the next, there is the principal need to investigate if the effects on CSCs may be used to overcome cancer resistance and it will be opportune to consider whether molecular targeted therapies should be used alone or combined with conventional therapy, or with a different target drug specific for CSCs.     

Clopidogrel’s role in the management of atherosclerotic disease: a focus on acute coronary syndromes

Recent advances in our understanding of the role of the platelet in the atherosclerotic process beyond the acute formation of arterial blood clots, such as inflammation, have highlighted the role of antiplatelet agents as being much more than just ‘blood thinners.’ Some of the most important cardiovascular trials performed in the last 20 years have studied antiplatelet therapies. However, despite their long history, current global health implications and proven benefit, there remain substantial gaps in our understanding as to how to best utilize the limited number of antiplatelet agents available. This article will discuss the mechanism of action of the antiplatelet class known as thienopyridines, the pharmacodynamics and pharmacokinetics of the thienopyridine agent clopidogrel (Plavix^®, Bristol-Myers Squibb and Sanofi Pharmaceuticals) as well as the literature supporting its clinical benefits and areas of ongoing research that will help clarify the optimal utilization of clopidogrel for the treatment of cardiovascular disease.     

Investigating cell therapy for inflammatory bowel disease

ABSTRACT

Introduction: Advances in immuno-modulatory therapies, including anti-TNF-α therapies, have greatly increased the chance to achieve long-term remission of inflammatory bowel disease (IBD) patients. However, as the importance of mucosal healing has been demonstrated in a number of clinical studies, new cell-based therapies that can regenerate and fully restore the intestinal mucosal functions are currently under development.

Area covered: In this review, we feature the recent challenges of cell-based therapies that are applied to the treatment of IBD. In particular, we will focus on hematopoietic stem cells (HSC), mesenchymal stem cells (MSCs) and intestinal stem cells (ISCs) as the candidate source for cell-based therapy targeted to treat IBD. The current status, as well as the expected advantages and disadvantages of those transplantations will be summarized and discussed.

Expert opinion: Transplantation of HSC, MSC and ISC may have different levels of potential in their ability to exert an immunomodulatory or pro-regenerative effect. Combined cell therapies, such as co-transplantation of MSC and ISC, may provide improved therapeutic outcome compared to transplantation of a single cell population. Those cell-based therapies may not only improve the disease activity or tissue regeneration, but may also have the potential to decrease the risk of developing colitis-associated cancers.     

Clinical application of human CD4+ CD25+ regulatory T cells for the treatment of inflammatory bowel diseases

As our understanding of the immunological and genetic basis of inflammatory bowel disease (IBD) grows, potential therapeutic options are being developed at a rapid pace. Nevertheless, new drugs for IBD are needed because about half of all patients with severe ulcerative colitis (UC) eventually undergo colectomy, and a significant part of Crohn's disease (CD) patients do not respond to standard medical therapies, including immunosuppressants and TNF-alpha neutralising antibodies, or suffer from significant side effects. Finally, recurrence of disease activity following remission is frequent in both UC and CD, and there is an unmet need for effective maintenance strategies. It is well-known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only does active suppression by regulatory T (TR) cells play an important role in the normal intestinal homeostasis, but also its dysregulation might lead to the development of IBD. TR cells are functional subsets of T cells that downregulate adaptive immune responses by interfering with the activation of dendritic cells and proliferation of T cells. From experimental work it is now clear that TR cells play a critical role in maintaining immune homeostasis, and several therapeutic approaches have been targeted at the induction of TR cells in order to control mucosal inflammation. Before using TR cells clinically as living immunosuppressants for the treatment of IBD, however, we have to pass many critical checkpoints, such as the in vitro expansion of TR cells and the confirmation of their safety. This paper will discuss recently gained knowledge of human TR cells and the possibility of their clinical usages as a new strategy for the treatment of IBD.     

Advances in Diabetes Pharmacotherapy: An Update for the Emergency Provider

Background

Diabetes mellitus is a disease that affects millions of Americans, and its prevalence is only anticipated to increase in coming years. It is estimated that diabetes-related visits account for 1% of all emergency department (ED) encounters. In recent years, there have been several new categories of medications approved for the treatment of diabetes, including new insulins, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, an amylin analogue, and sodium-glucose cotransporter-2 inhibitors.

Recent advances in inflammatory bowel disease

The last decade has seen tremendous advances in our knowledge, which has led to genuine improvements in our understanding of the pathogenesis and management of inflammatory bowel disease (IBD). The combined power of cellular and molecular biology has begun to unveil the enigmas of IBD, and, consequently, substantial gains have been made in the treatment of IBD. Refinements in drug formulation have provided the ability to target distinct sites of delivery, while enhancing the safety and efficacy of older agents. Simultaneous progress in biotechnology has fostered the development of new agents that strategically target pivotal processes in disease pathogenesis. This article addresses our current understanding of the pathogenesis of IBD, including the latest developments in animal models and covers agents currently used in the treatment of IBD as well as emerging therapies.     

Emerging strategies to treat chronic immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is a fairly common hematological disorder and is a minor disease for many affected patients; most are in good health, and many can tolerate low platelet counts without the need for treatment. For the majority of patients who do undergo treatment, first-line therapies, including corticosteroids, are effective in increasing platelet counts, although long-term use can be associated with adverse effects. Second-line therapies, such as immunosuppressants, have been largely untested in controlled studies of ITP patients. Like first-line therapies, splenectomy is effective for many patients; however, it is frequently avoided by physicians who prefer the use of alternative drug therapies due to concerns about safety risks and is often declined by patients reluctant to undergo surgery. Thus, approaches to avoid or defer the use of splenectomy have been actively pursued. An anti-CD20 antibody, rituximab, can limit the production of autoantibodies, but reactivated viral infections have been reported with its use. Agents that directly stimulate platelet production, such as thrombopoietin (TPO) receptor-binding agents, have shown promise in clinical trials of ITP patients as well as in hepatitis C virus-infected individuals with thrombocytopenia. Two TPO receptor agonists in advanced clinical development--eltrombopag and AMG 531--are discussed here. Both eltrombopag and AMG 531 appear to be effective in raising platelet counts and both have been well tolerated in clinical trials to date. However, potential safety issues with thrombopoietic growth factors include thrombocytosis, rebound thrombocytopenia, and increased bone marrow fibrosis. Further testing will determine which safety issues--if any--are of clinical concern.     

Web-based learning in inflammatory bowel diseases: General truths and current specifics

In a field rapidly evolving over the past few years, the management of inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, is becoming increasingly complex, demanding and challenging. In the recent years, IBD quality measures aiming to improve patients’ care have been developed, multiple new medical therapies have been approved, new treatment goals have been set with the “treat-to-target” concept and drug monitoring has been implemented into IBD clinical management. Moreover, patients are increasingly using Internet resources to obtain information about their health conditions. The healthcare professional with an interest in treating IBD patients should deal with all these challenges in everyday practice by establishing, enhancing and maintaining a strong core of knowledge and skills related to IBD. This is an ongoing process and traditionally these needs are covered with additional reading of textbook or journal articles, attendance at meetings or conferences, or at local rounds. Web-based learning resources expand the options for knowledge acquisition and save time and costs as well. In the new era of communications technology, web-based resources can cover the educational needs of both patients and healthcare professionals and can contribute to improvement of disease management and patient care. Healthcare professionals can individually visit and navigate regularly relevant websites and tailor choices for educational activities according to their existing needs. They can also provide their patients with a few certified suitable internet resources. In this review, we explored the Internet using PubMed and Startpage (Google), for web-based IBD-related educational resources aiming to provide a guide for those interested in obtaining certified knowledge in this subject.     

结缔组织病相关肺动脉高压的早期诊断与治疗

肺动脉高压是结缔组织病患者最为严重的并发症之一,影响到最多达15%的结缔组织病患者,预后很差,已有证据显示在结缔组织病患者中早期发现肺动脉高压进而早期开始治疗能够改善患者的预后。除常用的超声心动图外,近年来已有一些生化标记物、肺功能检查及心电图指标等被发现有助于早期筛查肺动脉高压,也有一些联合多种参数的筛查流程问世。治疗方面肺动脉靶向药物包括内皮素受体拮抗剂、前列环素类似物以及磷酸二酯酶-5抑制剂均被证实对于治疗结缔组织病相关肺动脉高压有效。本综述的目的是描述结缔组织病相关肺动脉高压的发病及临床特点、早期诊断及治疗,着重强调最新发表的一系列早期筛查方法以及已经被证实的治疗药物。     

2010: year in review

This section of Headache annually reviews the status of recently completed and ongoing clinical trials involving headache disorders. The review will focus on multicenter trials of new therapies as well as novel formulations of previously approved therapeutics. Table 1 summarizes major migraine therapeutic trials that have been completed recently, according to data obtained from the "ClinicalTrials.Gov" website as well as from corporate press releases. Table 2 summarizes the major therapeutic trials that are ongoing at the present time.     

Medical applications of transforming growth factor-beta

Transforming growth factor-beta (TGF-beta) proteins and their antagonists have entered clinical trials. These multi-functional regulators of cell growth and differentiation induce extracellular matrix proteins and suppress the immune system making TGF-betas useful in treatment of wounds with impaired healing, mucositis, fractures, ischemia-reperfusion injuries, and autoimmune disease. In diseases such as keloids, glomerulonephritis and pulmonary fibrosis, excessive expression of TGF-beta has been implicated as being responsible for accumulation of detrimental scar tissue. In these conditions, agents that block TGF-beta have prevented or reversed disease. Similarly, in carcinogenesis, blocking TGF-beta activity may be valuable in stimulating an immune response towards metastasis. As these blocking agents receive approval, we will likely have new therapies for previously recalcitrant diseases.     

Novel therapies in benign and malignant bone diseases

With an ageing population and improving cancer therapies, the two most common benign and malignant bone diseases, osteoporosis and bone metastases, will continue to affect an increasing number of patients. Our expanding knowledge of the molecular processes underlying these conditions has resulted in novel bone targets that are currently being explored in clinical trials. Clearly, the approval of denosumab, a monoclonal antibody directed against RANKL, has just marked the beginning of a new era for bone therapy with several additional new therapies lining up for clinical approval in the coming years. Potential agents targeting the osteoclast include cathepsin K, currently in phase 3 trials, and src inhibitors. Amongst anabolic agents, inhibitors of the Wnt-inhibitor sclerostin and dickkopf-1 are promising in clinical trials. Here, we will provide a comprehensive overview of the most promising agents currently explored for the treatment of bone diseases.     

Overview of anti-VEGF therapy and angiogenesis. Part 1: Angiogenesis inhibition in solid tumor malignancies

Several new agents that target the vascular endothelial growth factor (VEGF) pathway and inhibit angiogenesis are emerging as promising therapies in multiple cancer types. Bevacizumab, a humanized monoclonal antibody to VEGF-A, is currently approved in combination with intravenous 5-fluorouracil-containing regimens for the first-line treatment of metastatic colorectal cancer and recently demonstrated clinically important results in combination with chemotherapy in patients with non-small cell lung cancer and metastatic breast cancer. Other anti-VEGF agents that have shown benefit in various cancer types will be discussed in this monograph. Despite the often striking results observed with anti-VEGF agents, several unanswered questions remain, such as the optimal duration of therapy and patient selection criteria. These other issues, including the biologic rationale for anti-VEGF therapy, as well as recent clinical trial data with anti-VEGF agents in colorectal, pancreatic, lung, kidney, and brease cancers, are discussed.